Nephrogenic systemic fibrosis

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Nephrogenic systemic fibrosis

Nephrogenic systemic fibrosis (NSF) or nephrogenic fibrosing dermopathy (NFD)[1] is a rare and serious syndrome that involves fibrosis of skin, joints, eyes, and internal organs. The first cases were identified in 1997 and its cause is not fully understood. However, evidence suggests NSF is associated with exposure to gadolinium (with gadolinium-based MRI contrast agents being frequently used as contrast agents for magnetic resonance imaging (MRI)) in patients with severe kidney failure.[2] Epidemiological studies suggest that the incidence of NSF is unrelated to gender, ethnicity, or age and it is not thought to have a genetic basis. A registry for NSF has identified about 335 cases as of 2011.[3]

Most patients with NSF have undergone hemodialysis for kidney failure, some have never undergone dialysis and others have received only peritoneal dialysis. Many people with NSF have taken immunosuppressive medications and have other diseases, such as hepatitis C. Four of the seven gadolinium contrast agents approved by the U.S. Food and Drug Administration have been principally implicated in NSF, including gadodiamide, gadopentetate, and gadoversetamide. Gadobenate has also been associated with NSF, but further research has shown that gadobenate diglumine might be safe even in patients undergoing dialysis.[4]

Signs and symptoms[edit]

In NSF, patients develop large areas of hardened skin with fibrotic nodules and plaques. NSF may also cause joint contractures resulting in joint pain and limitation in range of motion. In its most severe form, NSF may cause severe systemic fibrosis affecting internal organs including the lungs, heart and liver.[5][6]

Associated conditions[edit]

NSF has also developed in patients with acute kidney injury,[medical citation needed] even if kidney function subsequently returned to normal following GBCM administration [15]. In one series, up to 20% of NSF cases were diagnosed in patients who had been in some element of transient acute kidney failure (often, but not always, superimposed upon chronic kidney disease) at the time of GBCM administration.[7]

This classification was released after another proposition would have left the safest category (ionic cyclical structure) with only one agent (Dotarem). The intermediate category would have been both ionic linear structure and non-ionic cyclical structure. The third category most at risk was unchanged (linear non-ionic).[8]

Risk factors[edit]

The European Medicines Agency has classified the gadolinium-containing contrast agents into three risk groups:[9]

The suitability of gadolinium complexes as magnetic resonance imaging contrast agents depends on a number of factors. A thermodynamic relationship to toxicity exists if one assumes that the chemotoxicity of the intact complex is minimal but that the toxicity of the components of the complex (free metal and uncomplexed ligands) is substantial.

Release of Gd(III) from the complex is responsible for the toxicity associated with gadolinium complexes; this release appears to be a consequence of Zn2+, Cu2+, and Ca2+ transmetallation in vivo. This hypothesis is supported by acute toxicity experiments, which demonstrate that despite a 50-fold range of LDse values for four Gd(III) complexes, all become lethally toxic when they release precisely the same quantity of Gd(III). It is also supported by subchronic rodent toxicity experiments, which demonstrate a set of gross and microscopic findings similar to those known to be caused by Zn2+ deficiency. Finally, this hypothesis predicts that subtle changes in formulation can further enhance the intrinsic safety of these complexes. The added Ca2+ salt of the ligand must have a favorable toxicity so that the decrease in toxicity from in vivo transmetallation is not offset, or overcome, by the addition of a toxic component to the formulation.[10]


Microscopic pathology[edit]

At the microscopic level, NSF resembles scleromyxedema. Both conditions show a proliferation of dermal fibroblasts and dendritic cells, thickened collagen bundles, increased elastic fibers, and deposits of mucin.[11] More recent case reports have described the presence of sclerotic bodies (also known as elastocollagenous balls) in skin biopsies from NSF patients. While not universally present, this finding is believed to be unique to patients exposed to gadolinium, although not necessarily limited to areas involved by NSF.[12][13][14]



The first cases of NSF were identified in 1997,[15] but NSF was first described as an independent disease entity in 2000.[16] While skin involvement is on the foreground, the process may involve any organ and resembles diffuse scleroderma or systemic sclerosis.[17] In 2006, the link between NSF and gadolinium-containing contrast agents was made.[18][19][20] As a result, gadolinium-containing contrast is now considered contraindicated in patients with an estimated glomerular filtration rate (a measure of renal function) under 60 and especially under 30 ml/mn.[21] One retrospective study of the Veterans Affairs Electronic Medical Record found no cases of NSF among 141 patients receiving hemodialysis for chronic kidney disease who received gadoteridol.[22]


  1. ^ "SSA - POMS: DI 23022.835 - Nephrogenic Systemic Fibrosis - 08/10/2012". Retrieved 2016-01-12. 
  2. ^ Thomsen HS (2009). "Nephrogenic systemic fibrosis: history and epidemiology". Radiol Clin North Am. 47 (5): 827–31. doi:10.1016/j.rcl.2009.05.003. 
  3. ^ The NSF registry site.
  4. ^ Nandwana, Sadhna B.; Moreno, Courtney C.; Osipow, Michael T.; Sekhar, Aarti; Cox, Kelly L. (September 2015). "Gadobenate Dimeglumine Administration and Nephrogenic Systemic Fibrosis: Is There a Real Risk in Patients with Impaired Renal Function?". Radiology. 276 (3): 741–747. doi:10.1148/radiol.2015142423. PMID 25875973. 
  5. ^ Kucher C, Steere J, Elenitsas R, Siegel DL, Xu X (2006). "Nephrogenic fibrosing dermopathy/nephrogenic systemic fibrosis with diaphragmatic involvement in a patient with respiratory failure". J Am Acad Dermatol. 54: S31–34. doi:10.1016/j.jaad.2005.04.024. 
  6. ^ Krous H, Breisch E, Chadwick AE, Pinckney L, Malicki DM, Benador N (2007). "Nephrogenic systemic fibrosis with multiorgan involvement in a teenage male after lymphoma, Ewing's sarcoma, end-stage renal disease, and hemodialysis". Pediatr Dev Pathol. 10: 395–402. doi:10.2350/06-05-0093.1. 
  7. ^ Revision performed with input from and approval of the ACR Subcommittee on MR Safety, Nephrogenic Systemic Fibrosis,
  8. ^
  9. ^ Medicines and Healthcare products Regulatory Agency. Drug Safety Update, August 2007 pg 2-4. Link Archived 2008-10-09 at the Wayback Machine. (121 KB)
  11. ^ Scheinfeld, NS; Cowper, S; Kovarik, CL; Butler, DF. "Nephrogenic Systemic Fibrosis." Emedicine. [1]
  12. ^ Bhawan J, Perez-Chua TA, Goldberg L (Sep 2013). "Sclerotic bodies beyond nephrogenic systemic fibrosis". J Cutan Pathol. 40 (9): 812–7. doi:10.1111/cup.12187. 
  13. ^ Bhawan J, Swick BL, Koff AB, Stone MS (2009). "Sclerotic bodies in nephrogenic systemic fibrosis: a new histopathologic finding". J Cutan Pathol. 36 (5): 548–52. doi:10.1111/j.1600-0560.2008.01111.x. 
  14. ^ Wiedemeyer K, Kutzner H, Abraham JL, Thakral C, Carlson JA, Tran TA, Hausser I, Hartschuh W (2009). "The evolution of osseous metaplasia in localized cutaneous nephrogenic systemic fibrosis: a case report". Am J Dermatopathol. 31: 674–681. doi:10.1097/dad.0b013e3181a1fb55. 
  15. ^ Cowper SE (2003). "Nephrogenic fibrosing dermopathy: the first 6 years". Current Opinion in Rheumatology. 15 (6): 785–790. doi:10.1097/00002281-200311000-00017. PMID 14569211. 
  16. ^ Cowper SE, Robin HS, Steinberg SM, Su LD, Gupta S, LeBoit PE (2000). "Scleromyxoedema-like cutaneous diseases in renal-dialysis patients". Lancet. 356 (9234): 1000–1. doi:10.1016/S0140-6736(00)02694-5. PMID 11041404. 
  17. ^ Mendoza FA, Artlett CM, Sandorfi N, Latinis K, Piera-Velazquez S, Jimenez SA (2006). "DESCRIPTION OF TWELVE CASES OF NEPHROGENIC FIBROSING DERMOPATHY AND REVIEW OF THE LITERATURE". Semin. Arthritis Rheum. 35 (4): 238–49. doi:10.1016/j.semarthrit.2005.08.002. PMC 1434722Freely accessible. PMID 16461069. 
  18. ^ Grobner T (2006). "Gadolinium--a specific trigger for the development of nephrogenic fibrosing dermopathy and nephrogenic systemic fibrosis?". Nephrol. Dial. Transplant. 21 (4): 1104–8. doi:10.1093/ndt/gfk062. PMID 16431890. 
  19. ^ Marckmann P, Skov L, Rossen K, et al. (2006). "Nephrogenic systemic fibrosis: suspected causative role of gadodiamide used for contrast-enhanced magnetic resonance imaging". J. Am. Soc. Nephrol. 17 (9): 2359–62. doi:10.1681/ASN.2006060601. PMID 16885403. 
  20. ^ Centers for Disease Control and Prevention (CDC) (2007). "Nephrogenic fibrosing dermopathy associated with exposure to gadolinium-containing contrast agents--St. Louis, Missouri, 2002-2006". MMWR Morb. Mortal. Wkly. Rep. 56 (7): 137–41. PMID 17318112. 
  21. ^ Kanal E, Barkovich AJ, Bell C, et al. (2007). "ACR guidance document for safe MR practices: 2007". AJR. American journal of roentgenology. 188 (6): 1447–74. doi:10.2214/AJR.06.1616. PMID 17515363. 
  22. ^ Reilly, Robert (May 2008). "Risk for Nephrogenic Systemic Fibrosis with Gadoteridol (ProHance) in Patients Who Are on Long-Term Hemodialysis". Clin J Am Soc Nephrol. 3. 3 (3): 747–751. doi:10.2215/CJN.05721207. PMC 2386692Freely accessible. PMID 18287249. 

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